title: Lymphotoxin α induces apoptosis, necroptosis and inflammatory signals with the same potency as tumour necrosis factor.
abstract: Both of the TNF superfamily ligands, TNF and LTα, can bind and signal through TNFR1 and TNFR2, yet mice mutant for each have different phenotypes. Part of this difference is because LTα but not TNF can activate Herpes Virus Entry Mediator and also heterotrimerise with LTβ to activate LTβR, which is consistent with the similar phenotypes of the LTα and LTβR deficient mice. However, it has also been reported that the LTα3 homotrimer signals differently than TNF through TNFR1, and has unique roles in initiation and exacerbation of some inflammatory diseases. Our modeling of the TNF/TNFR1 interface compared to the LTα3/TNFR1 structure revealed some differences that could affect signalling by the two ligands. To determine whether there were any functional differences in the ability of TNF and LTα3 to induce TNFR1-dependent apoptosis or necroptosis, and if there were different requirements for cIAPs and Sharpin to transmit the TNFR1 signal, we compared the ability of cells to respond to TNF and LTα3. Contrary to our hypothesis, we were unable to discover differences in signalling by TNFR1 in response to TNF and LTα3. Our results imply that the reasons for the conservation of LTα are most likely due either to differential regulation, the ability to signal through Herpes Virus Entry Mediator or the ability of LTα to form heterotrimers with LTβ.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, University of Melbourne, Parkville, Australia.
authors.forename: Nima
authors.initials: N
authors.lastname: Etemadi
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Holien
authors.forename: Diep
authors.initials: D
authors.lastname: Chau
authors.forename: Grant
authors.initials: G
authors.lastname: Dewson
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Michael W
authors.initials: MW
authors.lastname: Parker
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Ueli
authors.initials: U
authors.lastname: Nachbur
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D047468:Immunoprecipitation; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008233:Lymphotoxin-alpha / Q000737:chemistry / Q000494:pharmacology*; D053308:Lymphotoxin-beta / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D011487:Protein Conformation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000737:chemistry / Q000378:metabolism*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha
keywords: apoptosis; inflammation; lymphotoxin α; necroptosis; tumour necrosis factor